We propose to continue investigation of the genetics of autosomal dominant partial epilepsy with auditory features (ADPEAF), a form of idiopathic lateral temporal lobe epilepsy with auditory disturbances as a major focal seizure manifestation. In 1995 we mapped the susceptibility locus for this syndrome to a 10cM interval on chromosome 10q24 in a single large pedigree. The goals of the initial phase of our study (4/1/97- 3/31/2001) were to refine the genetic localization, assess locus heterogeneity, and define the range of seizure disorders resulting from the gene. This work progressed more rapidly than anticipated, and in January 2002 we reported the identification of the gene that causes this syndrome, LGI1, in five ADPEAF families. In the next phase of the study, we plan to investigate the role of mutations in LGI1 in idiopathic epilepsy with auditory features, both in families containing multiple affected individuals and in isolated cases. We will ascertain, clinically characterize, and sample approximately 100 new families containing >1 individual with idiopathic partial epilepsy with auditory features. To identify mutations of potential functional significance, we will sequence the gene's coding regions and intron-exon junctions in one affected individual in each family. If we identify putative disease-related variants, we will evaluate their impact on the protein, investigate cosegregation with disease in the families, and compare their frequency with that in an ethnically matched control sample. We will also investigate factors that predict whether or not a family carries a variant (e.g., number of affected family members, number with auditory or other symptoms, age at onset), compute penetrance of the identified variants, compare the types of variants found in isolated cases vs. families containing multiple affected individuals, and assess the effect of variants on risk for seizure disorders other than idiopathic partial epilepsy (symptomatic epilepsy, febrile seizures, other acute symptomatic seizures). We will also assess the role of mutations in LGI1 in 89 families with other types of epilepsy, which have already been collected as part of a separate study. Some of these families contain individuals with partial epilepsy with auditory symptoms, and will be assigned the highest priority for this assessment. Finally, we will evaluate clinicatmanifestations of LGtl mutations in additional studies of mutation carriers with epilepsy, mutation carriers without epilepsy, and noncarriers, including reinterview to ascertain new onset of seizures since our previous interviews and subtle manifestations of seizures that may have been missed previously, and performance of MRI studies to detect subtle cortical malformations that might result from mutations in the gene.